Mutational spectrum defines primary and secondary myelofibrosis.

E ssential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome-negative myeloproliferative neoplasias (Ph-MPN). MPNs are clonal bone marrow stem cell disorders involving a multipotent hematopoietic stem cell, characterized by proliferation of one or more lineages of the myeloid, erythroid and megakaryocytic cell lines. This proliferation results in increased numbers of granulocytes, erythrocytes or platelets in the peripheral blood, respectively. The most prevalent mutation in MPN is the JAK2-V617F mutation, discovered in 2005. 1-4 Approximately 95% of PV patients, 50-70% of ET patients and 40-50% of PMF patients possess this specific JAK2 mutation. The JAK2-V617F mutation is located in exon 14 of the gene and abrogates the negative regulatory activity of the pseudokinase domain JH2 of the encoded JAK2 tyrosine kinase. 5 Therefore, this mutation leads to a consti-tutive active JAK2 kinase signaling which is independent of cytokine stimulation. Hematopoiesis is regulated mainly by hematopoietic cytokines, such as granulocyte colony stimulating factor (GCSF), erythropoietin (EPO) or thrombopoietin (TPO). Mutated genes found in MPNs frequently target these cytokine signaling pathways with mutations in the JAK2 gene being the most prominent. Myeloproliferative leukemia virus oncogene (MPL) encodes the receptor for TPO, which mediates signaling through the JAK-STAT pathway and several gain-of-function mutations in exon 10 are seen in JAK2-V617F negative ET and PMF patients. Loss-of-function mutations of the adaptor protein LNK (SH2B3), which negatively regulates the TPO and EPO cytokine signaling, have been reported at low frequency in JAK2-V617F negative MPN patients. Other signaling mutations have also been reported in SOCS, and CBL, NRAS as deletions of NF1. Mutations of genes involved in RNA splicing, such as SF3B1, SRSF2, U2AF1, have been identified in myelodysplastic syndrome (MDS) and MPN patients. 6 Gene expression regulators, such as transcription factors, are deleted or mutated in MPN, suggesting a critical function in MPN pathogenesis. IKZF1, which encodes the transcription factor Ikaros, is a target of chromosome 7p deletions in MPNs, and a late event in the clonal evolution from MPN to sAML. Other transcription factors are involved in chromosomal deletions: FOXP1 and del 3p, ETV6 and deletions on chromosome 12p, and CUX1 and chromosome 7q deletions. In addition, the transcription factor p53 was found to be mutated in a small proportion of patients, 7 and RUNX1 has been reported to be mutated in AML, post-MDS-AML and post-MPN AML. 8 Furthermore, various genes involved in epigenetic mechanisms can be …